Teaching T Cells to Tolerate Friends

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Teaching the immune system to tolerate certain friendly bacteria is an important step towards gut health, and this week researchers in America have shed some light on how and where those lessons take place.

There is a well-known and understood way of training the immune system, which occurs in an organ called the thymus. Special immune cells, known as T cells, are generated with a wide range of antigen receptor molecules on their surface that are used to recognise and attach to other molecules. Some of these would interact with our own cells, leading to auto-immune diseases but in the thymus these receptors are checked and sorted, with the non self-reactive T cells maturing into T effector cells, to play a role in identifying and attacking infection. The self-reactive T cells are either destroyed or matured into regulatory cells or Treg cells, which keep other components of the immune system in check.

Working with mice, Chyi-Song Hsieh and colleagues at Washington University School of Medicine, showed that an encounter between immature T cells and commensal, or friendly, gut bacteria could also lead to the creation of Treg cells and, therefore, teach the immune system to hold fire. This education happens directly at the site of the encounter - the gut.

The researchers noticed that Treg cells around the colon used different antigen receptors from those in other locations, and that these seemed to correlate with the gut bacteria themselves, interpreting the bacteria in a similar way to how Treg cells elsewhere interpret 'self'.

They then wanted to find out if these receptors were actually learned from the bacteria, and not just from the mouse itself. To do so, they transferred the genes that code for these receptors into the bone marrow of modified mice that do not normally produce T cells. This then caused them to produce immature T cells expressing the right receptors, but these cells didn't mature into Treg as expected. They realised that as the modified mice had been delivered from elsewhere, they would have developed different gut bacteria, so only when they housed all the mice together, allowing them to share bacteria, did these Treg cells mature. This showed that the presence of the bacteria themselves is essential for this immune training process to work.

Hsieh also noticed that in mice with colitis, an inflammatory condition of the bowel, these receptors were not present on Treg cells, but rather on effector T cells, which encourage an adverse reaction to the bacteria. It's suggested that breakdown in this immune education process might similarly lead to ulcerative colitis and Crohn's disease in humans.

Although the exact mechanism for how the bacteria train the T cells is still unknown, this paper, published in Nature, marks an important step forward and the first in-vivo demonstration of T cell education outside the thymus, as well as suggesting new ways to approach the treatment of these diseases.